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Biosimilars: History
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Contributor: Sarfaraz K. Niazi

Biosimilars are recombinant DNA products that join DNA from different species and subsequently insert the hybrid DNA into a host cell, often a bacterium or mammalian cell, to express the target protein; this molecular chimera was first created by researchers from UC San Francisco and Stanford in 1972. Stanley Cohen of Stanford and Herbert Boyer of UCSF received the US patent in 1980. Boyer co-founded Genentech, Inc. in 1976. The Cohen-Boyer patents will eventually have more than 500 licensees to biotechnology and pharmaceutical companies and earn Stanford and UCSF more than USD 250 million in royalties. These patents have now expired. Biosimilars include monoclonal antibodies, cytokines, growth factors, enzymes, immunomodulators, and thrombolytics, proteins extracted from animals or microorganisms, including recombinant versions of these products (except clotting factors), and other non-vaccine therapeutic immunotherapies. Billions of patients receiving biosimilars have shown therapeutic equivalence. None of these products have shown adverse events more than the reference product, including immunogenicity responses. It is estimated that the cumulative exposure to EU-approved biosimilars was more than two billion patient treatment days in 2020, with no adverse event reporting or withdrawal from the market due to safety reasons and no biosimilar-specific adverse effects have been added to the product information.

  • biosimilars
  • WHO
  • analytical assessment
  • biological drugs
  • FDA

1. Regulatory Background

1.1. The US Scene

There are over 100 biosimilar programs enrolled with the FDA [1]. To expedite the approval process, the FDA has taken several significant steps.
The FDA has created two new guidelines, the extension of the Q&A presentations [2] and the third revised draft guidance [3] titled “New and Revised Draft Q&As on Biosimilar Development and the BPCI Act”. The details refer to fulfilling pediatric assessment or PREA requirements, post-approval filing, and asserting that the 351(k) cannot have a different route or dosage form. However, the strength issue was delayed, adding new indications and orphan exclusivity. The FDA also updated The Purple Book FAQ section [4].
FDA has also published new fact sheets to provide additional educational materials on biosimilar and interchangeable products and the biosimilar regulatory review and approval process.
The BPCIA states [5] that the “Secretary may determine, in the Secretary’s discretion, that an element described in clause (i) (I) [the biosimilar testing] is unnecessary in an application submitted under this subsection”. The FDA has subtly implemented this change in its new biosimilar guidance. However, unlike the EMA, MHRA, or WHO, the FDA is bound by the BPCIA legislation that states that “an application submitted under this subsection shall include information demonstrating that the biological product is biosimilar to a reference product based upon data derived from analytical studies, animal studies, and clinical studies”. The new education material includes the phrase “in addition to analytical studies, other studies that may be needed”, not shall be, as stated in the BPCIA.
The FDA posts details of its approval of biosimilar products. However, a biosimilar developer may object and secure under the Freedom of Information Act [6].

1.2. The EMA Scene

In 2001, much of the EU’s directive-based legislation concerning the regulation of medicines was codified as Directive 2001/83/EC. The EMA has issued concept papers, draft guidance, and public scientific workshops. The EMA’s Committee for Medicinal Products for Human Use (CHMP) has also issued product class-specific guidance such as recombinant erythropoietin, granulocyte-colony stimulating factor, recombinant human soluble insulin, low-molecular-weight heparins, somatropin, and recombinant interferon alfa [7]. However, EMA has announced that they intend not to issue more specific biosimilar guidelines but instead prefer to give tailored advice on a case-by-case basis. This change in the EMA policy came from the FDA, and such guidelines can misdirect the development of biosimilars.
Patents are not a significant issue in the EMA filing; the litigation is left to the claiming parties. The patent laws in the EU are also different. The exclusivity for biological drugs is ten years in the EU and 12 years in the US, giving the EU filings at least a two-year head start. However, the ten years of exclusivity for patents and other exclusivity rights can last longer than ten years after market approval. In the EU, process patents are rarely awarded, reducing the significant barrier experienced by US filings, where the patent dance involves the product and a multitude of process patents. The differences in the patent laws between the US and the EU significantly impact the speed and scope of introducing biosimilars. This topic is of interest to determine whether a harmonized guideline should include the intellectual property issue, as elaborated later [8].
EMA guidelines and the decision-making of the EMA in approving biosimilars have evolved significantly; the EMA is now promoting removing animal testing, though it is not yet been made clear. In addition, like the FDA, EMA has recently begun approving biosimilars without requiring clinical efficacy testing.

1.3. The WHO Scene

The World Health Organization (WHO) is not a regulatory authority, but it is mandated to support regulatory authorities in its 194 Member States. The WHO guidelines on evaluating biosimilars [9] provide suggestions to National Regulatory Agencies (NRAs) principles for approving biosimilars.
In 2019, the WHO Expert Committee on Biological Standardization (ECBS) considered that a more tailored and potentially reduced clinical data package might be acceptable in cases where the available scientific evidence supported this. In addition, the committee endorsed the review of current scientific evidence to consider updating the Guidelines to provide more flexibility and clarity. Thus, the WHO reviewed scientific evidence and experience to identify issues/cases for further reducing non-clinical and clinical data. The progress was reported to the committee in 2020 (72nd and 73rd report) [10]. It has resulted in additional suggestions on evaluating biosimilar monoclonal antibodies (mAbs) and an expanded Q&A document.
In April 2022, the WHO published [11] a revised guideline based on the 22 comments received. While the newest guideline and suggestions made by the WHO represent the views of global regulatory agencies, it still falls short of establishing a rational scientific platform. Listed below are some of the notable shortcomings in the WHO understanding that should not be made part of a harmonized guideline:
  • The WHO states that “the clinical data should be generated using the biosimilar product derived from the final manufacturing process, reflecting the product for which authorization is being sought. Any deviation from this recommendation must be justified, and additional data may be required. For changes in the manufacturing process, relevant guidelines like the ICHQ5E should be followed”. However, the ICH comparability guideline applies only to the changes in the manufacturing of a biotechnology product that has already been approved and thus requires testing the product before and after the change, not with the reference product. To avoid confusion, the FDA has made a strong point by labeling these studies as “analytical assessments,” not even analytical comparisons.
  • In its earlier guidelines, the WHO had indicated no need for any statistical modeling of the critical quality attribute comparisons. The recent draft suggests using statistical modeling but warns about the risks of employing statistical tests on limited samples (false-positive and false-negative conclusions). This reluctance of the WHO to propose solid statistical modeling has resulted in many agencies requiring only 3–4 lots [12] for testing. It is well understood that a larger number of lots are required before the statistical modeling can be initiated. The WHO also states that the most frequently applied overall similarity criteria require that a certain percentage of the biosimilar batches (usually between 90% and 100%) fall within the similarity range. Given that in an equivalence range, 90% of biosimilar lots must fall within three standard deviations for the reference product. This means that only one lot out of ten can fall outside the range, but if there are less than ten lots tested, the analysis becomes moot.
  • For efficacy studies, the WHO allows using a non-inferiority model discouraged by the FDA and EMA as inappropriate to consider higher efficacy leading to higher safety issues.
  • The WHO suggests that the chosen reference product must have been marketed for a “suitable period” with proven quality, safety, and efficacy to serve the reference product. No suitable period is defined, and the advice has led to distrust in the safety of biological drugs approved under stringent regulatory compliance. While there is a 12-year restriction in the US and ten years in the EU, the WHO member agencies do not have to comply with this restriction. The WHO statement has caused great damage to the adoption of biosimilars in developing countries, and it must be removed.
  • The WHO suggests that a biosimilar developer may use one source of reference product for analytical testing and another for clinical testing. This argument is illogical; all testing should be performed using the same reference product derived from the same manufacturing source and bearing the same approval designation.
  • The WHO maintains its position, despite many criticisms, that regional agencies can decide the labeling and prescribing information. This is not only improper, but it is also unethical, giving the regulatory agencies to modify the safety and efficacy disclosures. The FDA has provided details of how the prescribing information should be developed; this should be followed by the WHO.
  • According to the WHO, if a comparison reveals differences in product-related substances and impurities between the biosimilar and the reference product, the impact of the differences on the clinical performance of the drug product (including its biological activity) should be evaluated. This is the most misguiding advice. A reference product had been thoroughly tested with its impurity profile for safety and efficacy. Unmatched impurities cannot be validated by any means, including animal testing or clinical efficacy testing. The quantity of matched impurities can vary, within certain limits, as they can only bring a change in efficacy that is not likely to be significant. This argument extends to process-related impurities as well. The process-related impurities can be adjusted; thus, there is little rationale for qualifying an impurity not present in the reference product. If a biosimilar product production can remove these uncertainties, it should, regardless of their assumed risk.
  • In the past, the WHO had given little importance to accelerated or stress condition testing; this is now changed to follow the rationale that these testing are meant to be part of the analytical assessment.
  • The WHO statement, “It is up to the manufacturer to justify the relevance of the established similarity ranges and criteria”, is inappropriate. These determinations should be based on scientific principles, not individual agency preferences. This advice from the WHO has resulted in the NRAs adopting irrational test limits without justification.
  • The WHO statement, “Nevertheless, any quality attributes not fulfilling the established similarity criteria should be considered a potential signal for non-similarity and assessed for possible impact on clinical safety and efficacy”, invites developers to seek waivers based on animal or clinical testing. Here, the WHO goes back to the assumption that differences in analytical similarity can be justified through any non-clinical or clinical study.
  • WHO states, “Based on the totality of quality and nonclinical in vitro data available and the extent to which there is residual uncertainty about the similarity of a biosimilar and its reference product, it is at the discretion of the involved NRA to waive or not to waive a requirement for additional nonclinical in vivo animal studies”. This statement is misleading as it has caused many agencies to develop extensive animal testing, such as the Indian CDSCO [12], which suggests using several times the human dose to establish safety. The WHO further states, “To address the residual uncertainties, the use of conventional animal species and specific animal models (for example, transgenic animals or transplant models) may be considered”. This is not sound scientific advice, leaving an impression that it may be possible to resolve differences in analytical similarity using tests without relevance.
  • WHO suggests that local tolerance studies are not required unless excipients are introduced for which there is little or no experience with the intended clinical route of application. Biosimilars can have formulations different from the reference product, and a tolerance study is required to evaluate the formulation. If a formulation includes ingredients that have not been used before, this creates significant risk and cannot be resolved.
  • According to the WHO, “Clinical studies should be designed to demonstrate confirmative evidence of the similar clinical performance of the biosimilar and the reference product, and therefore need to use testing strategies that are sufficiently sensitive to detect any clinically relevant differences between the products”. The testing strategies are always the same, either a response on a clinical marker. Both are the least sensitive to tell the difference compared to analytical assessment and clinical pharmacology testing.
  • Using reference products remains unclear with issues such as using a foreign reference product instead of a domestic product if a suitable reference product is not licensed locally. In this case, the NRA may accept a reference product that has been licensed in another jurisdiction.
  • If required by the legislation in place, the comparability of the local and foreign-sourced versions of the product should be demonstrated by analytical “bridging” studies and, where needed, complemented by additional PK/PD data. Here the WHO allows precedence of any local regulations to overcome scientific arguments.
  • The WHO statement, “It may also be prudent not to waive the efficacy and safety study when the reference product has common or unpredictable serious adverse effects that cannot be merely explained by exaggerated pharmacological action”, is based on the wrong assumption that efficacy study can overcome any unusual effects.
  • The WHO also allows the NRAs to develop their prescribing information, which leads to abuse of biosimilar products. There must be a unified approach to creating the label.

1.4. The MHRA Scene

Since exiting from Brexit, the MHRA has revised its guidelines independent of the EMA or ICH guidelines. As the end of the Brexit transition period approached last year, the MHRA released draft guidance for consultation that was finalized on 14 May 2022 [13]. This guideline has taken a more clear and more definite approach to the issues of animal testing and clinical efficacy evaluation.

1.5. The ROW Scene

Most countries follow the guidelines discussed above; however, the WHO members are more inclined to follow them unless they are more affluent, such as Saudi Arabia, where the FDA/EMA guidelines apply. Many countries treat biosimilars like generic chemical products with no clinical testing. In most cases, clinical testing is suggested for a fixed number of patients. Recently, the concept of biological API (active pharmaceutical ingredient) has risen, where companies import the drug substance and finish it locally.

2. Definitions

2.1. Terminology

The first step in harmonizing the regulatory guidelines requires uniformity in the terminology used in the context of biosimilar products. The terminology used in describing biosimilars and the testing requirements can make a difference in the scope of testing. For example, the term “biogeneric” was coined in 2004, but it was refused by the FDA on legal grounds adopting “biosimilars” instead [14]. The term “biosimilar” means biologically similar products, not otherwise, as it would be concluded if we call them similar biologicals.
Another term that needs attention is “comparability”, frequently used in place of “similarity” when comparing a biosimilar candidate’s structural or biological attributes with its reference product. The confusion starts with the ICH Guideline ICHQ5E [15] “Comparability of Biotechnological/Biological Products”, which is intended to qualify the changes in the manufacturing process of an approved biotechnology product, where the “comparability” is established between the products and before and after the change, not a reference product. Statements such as “for changes in the manufacturing process, relevant guidelines like the ICHQ5E should be followed” [10] by the WHO are misleading. It has caused developers to compare the development lots with their commercial product lots. The similarity assessment can only be made with the reference product; the “comparability” comes into the picture after a product has been approved. The FDA has made it more explicit by replacing “testing” with “assessment”.

2.2. Reference Product

What constitutes a reference product should be uniform—a product approved using a full dossier in one of the developed country’s regulatory agencies. This concept is not new; when generic drugs came into existence, the WHO concluded that “Comparator products should be purchased from a well-regulated market within the jurisdiction of a stringent regulatory authority (SRA). For WHO Medicines prequalification, an SRA is considered the regulatory authority of a country officially participating in the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and a member of ICH before 23 October 2015, namely: the US Food and Drug Administration, the European Commission and the Ministry of Health, Labor and Welfare of Japan also represented by the Pharmaceuticals and Medical Devices Agency. Therefore, the consensus that the reference biological product must be approved by one of the initial members of the ICH should be acceptable.
The WHO statement, “if the reference product is not authorized locally, the NRA may allow the use of a product licensed by an experienced NRA that follows the WHO or corresponding regulatory standards”, creates disharmony. The WHO further suggests bridging studies if the reference product is licensed locally but sourced from another jurisdiction.
There is a legal glitch in the BPCIA (FDA) that requires a reference product to be “licensed”, and biologicals are “licensed” only in the US. There are many cases where the same product is licensed in the US and authorized in the EU wherein “essentially” the same registration dossier is submitted for registration. The EU will not require a bridging study; the FDA has recently required a PK bridging study in such situations. The bridging studies, especially clinical PK/PD studies, have been criticized since they complicate the global development of biosimilars. The bridging studies should not be conducted if the reference comparator has been approved in any ICH jurisdiction and there is evidence in the public domain that the reference product has been approved in both jurisdictions upon some of the same phase III clinical data” [16]. It is doubtful that the EU- and US-sourced reference products have meaningful differences [17].
Health Canada permits using a foreign-sourced reference product licensed in an ICH country when it does not have a locally sourced product [18].
A foreign-sourced reference product can be used in clinical studies. This is the case for the EU and US, where a biosimilar must always refer to a local reference product for legal reasons. Still, clinical studies can be performed with a non-European Economic Area (EEA)/non-US version of the reference product, provided this has been authorized by a regulatory authority with similar scientific and regulatory standards. In this case, the FDA guidelines require analytical and PK/PD “bridging” studies by default. In contrast, the EMA and Health Canada guidelines require analytical bridging, but PK/PD bridging only if analytical bridging alone is insufficient.
The MHRA UK states that the reference product is sourced from the EU with evidence that the RP is licensed in the EU via the centralized, decentralized, or mutual recognition procedures, providing confirmation that these are the same as the Great Britain RP [12].

2.3. Materials and Standards

In-house Primary Reference Material: An appropriately characterized material prepared by the manufacturer from a representative lot(s) for biological assay and physicochemical testing of subsequent lots and against which in-house working reference material is calibrated.
In-house Working Reference Material: A material prepared similarly to the primary reference material established solely to assess and control subsequent lots for the individual attribute in question. It is always calibrated against the in-house primary reference material.
Publicly available reference standards (e.g., Ph. Eur.) cannot be used as the reference product for the demonstration of biosimilarity. However, using these standards is vital in method qualification and standardization.

3. Expression System

The Current US and EU guidelines allow the use of any expression system; however, if the expression system is not the same, at least to the extent it is described in the prescribing information (type, not necessarily the subtype), there can be many systematic issues with product quality that will require additional testing. In addition, in some instances, any “residual uncertainty” cannot be removed. The most widely used non-human host cell lines for recombinant expression are CHO, NS0, Sp2/0, HEK293, and PER.C6, BHK21), E. coli, and S. cerevisiae.
The developers are also advised to select an expression system that is more steady than productive; recently, very high-yielding cell lines have been developed, but when cell systems are pushed to produce, they also end up producing variants. Since the cost of goods of recombinant products is based on the carbon input, it may not significantly alter the cost. For example, the WHO calculates that the cost of production of monoclonal antibodies ranges from USD 95–200 per gram [19] given the current market price of 100–1000× the COGS; developers are advised to base their selection on cell lines that will allow for faster approval if they produce a consistent product. Furthermore, important are the considerations in the contamination of cell lines with antibiotics that should be avoided in their design.

4. Formulation

Biosimilars are allowed to have a formulation different from the reference product formulation. However, unless prevented by intellectual property, a formulation with the same or fewer inactive ingredients is preferred, notwithstanding any minor differences in the composition of ingredients. If a different formulation is used, it may contain new excipients that may not have been tested for the specific drug substance. If it is not used for the formulation of biological products of the same classification; all excipients must be free of animal materials; The formulation of the biosimilar should be selected considering state-of-the-art technology and does not need to be identical to that of the reference product. Regardless of the formulation selected, the suitability of the proposed formulation with regards to stability, compatibility (i.e., interaction with excipients, diluents, and packaging materials), integrity, activity, and strength of the active substance should be demonstrated. Suppose a different formulation and container/closure system to the reference product is selected (including any material in contact with the medicinal product). In that case, its potential impact on the efficacy and safety of the biosimilar should be appropriately justified.
Biosimilar epoetin α was the first epoetin α product that demonstrated the risk of neutralizing antibodies cross-reacting with endogenous erythropoietin, which has caused pure red cell aplasia in patients treated with the reference product [20]. This led to the discontinuation of the development of the product for subcutaneous administration until the underlying problem (which was not related to the quality of the active substance itself but tungsten leaching from the needle of the syringe) was eliminated. Thus, the licensed biosimilar epoetin α products have not shown excess immunogenicity compared to the reference product [21][22][23][24].
A novel excipient not used in the recombinant protein formulations should be avoided.
The use of excipient(s) in the proposed biosimilar product not used in the RP is not encouraged from a biosimilarity perspective. However, changes that may benefit patients (for example, reducing injection pain or stinging) are encouraged and should be carefully considered. Where different excipient(s) are used, there could be instances where this would be the first time that this route had used the excipient; a discussion should be presented addressing the safety of that excipient by the route intended.
In most instances, the excipient(s) will be used by the route intended at similar amounts to other products. If so, a discussion to establish this can be sufficient. However, suppose a novel excipient or a novel route for an excipient is used in the proposed biosimilar product. In that case, this should be justified and includes the possibility that results from new safety studies are presented, if appropriate. As studies intended to characterize the safety of the excipient, compliance with GLP is expected.

5. Release Specification

The first step in developing a biosimilar product is establishing the release specification drawn from the analysis of the reference product. Characterization of a biological product includes the determination of its physicochemical properties, biological activity, immunochemical properties, purity, and impurities using qualified testing methods. Testing a larger number of reference product lots is favorable to biosimilar developers, as it enables the justification of ranges of specifications that are more rational. The test lots can come from the lots used throughout the development process. However, at least one lot tested must be the one used for the first clinical trial, the PK/PD study.
The manufacturing process of the reference product evolves through its lifecycle, which may lead to detectable differences in some quality attributes. Such events could occur during the development of a biosimilar product. They may result in development according to a QTPP, which is no longer fully representative of the reference product available on the market. The ranges identified before and after the observed shift in quality profile could normally be used to support the biosimilar comparability exercise at the quality level, as either range represents the reference product. Quality attribute values outside or between the range(s) determined for a quality attribute of the reference product should be appropriately justified concerning their potential impact on safety and efficacy.
Many legacy attributes are independently established, such as sterility, invisible particles (a controversial issue with biosimilars to consider them as aggregates), protein content, potency, and physical properties specific to the biosimilar product; however, these remain controversial. For example, the commonly acceptable for having no more than 3% impurity and no single impurity more than 1% should be acceptable unless these ranges are higher, in which case, they must be justified. In addition, the impurities must not include any impurity not found in the reference product. Any concessions in this regard are the remnants of the understanding of the chemical products, where the immunological consideration is unimportant. Therefore, attempts to justify the safety of unmatched impurity are futile; it is better to remove the unmatched impurity.

6. Analytical Assessment

Analytical assessment is the strongest element of establishing biosimilarity. With newer analytical technologies, it is now a more vigorous exercise. Though the critical quality attributes are well-established, and so are the tests necessary, the developers have shown great discord in the choice of tests. For example, companies have submitted different numbers of analytical studies for adalimumab—25 by Pfizer and 71 by Boehringer—to achieve the same goal [25].
There is a disconnect between what constitutes orthogonal testing and what is duplicate testing. An orthogonal test is required if a validated or suitable test can provide aberrant results. For example, an HPLC method to measure protein content can be an orthogonal test to UV absorbance testing, but not another spectrometric test or another HPLC method. The validated methods are required for release testing but not for analytical assessment, and it is for this reason that side-by-side testing is needed and all testing at the same time.
The burden of analytical assessment can be significantly reduced if it is limited to quality parameters other than those included in the release specification. Every analytical assessment report of approved biosimilars uses release specification parameters in analytical assessment. For example, protein content or potency tests are release specification attributes.
The WHO does not consider a need for comparative stability profiling of the biosimilar candidate with the reference product. Because of differences in formulation, a biosimilar will have its lifecycle. Any process change post-approval should follow the ICH Q5E guideline. However, the stability of the biosimilar product should be determined according to ICH Q5C. The applicant should demonstrate that the desired product (including product-related substances) present in the finished product of the biosimilar is similar to that of the reference product. In contrast, process-related impurities may differ between the originator and biosimilar products, although these should be minimized. It is preferable to rely on purification processes to remove these impurities.
Product-related attributes are generally not modified by changing such parameters as upstream conditions; these are mostly driven by the expression system. Product-related attributes can and should be optimized; for example, one way to remove an unmatched impurity is to lose the yield and cut off the peak instead of justifying the impurity. The EU and UK fully agree with this suggestion [13].
The process-related attributes are not tested for analytical assessment; they are part of the release specification established by testing multiple lots of the reference product. However, any legacy attribute such as protein content or potency need not be tested in both instances.
Testing requires reference materials, and there have been many misconceptions about the role of pharmacopeias. Product release is based on using in-house reference materials, not on standards and reference materials (e.g., from Ph. Eur., WHO) that can only be used for method qualification and standardization.
An interesting example of disputes relates to the release of insulin products. The United States Pharmacopeia (USP) mandates an animal-based assay in rabbits in its Chapter “<121> Insulin Assays” (USP <121>) for the potency evaluation (biological activity) of insulin and insulin analogs. As the bioidentity test is mandatory in the US, it is included in the quality specification for insulin drug substances for the US market. Since physicochemical assays such as HPLC assays used to determine the content of human insulin and insulin analogs are much more precise and accurate than the rabbit blood sugar test, most of the Pharmacopeias (e.g., in Europe, Japan, and India) decided to forgo the testing in living animals. Consequently, the EMA recommends that marketing authorization holders use the chromatography method for insulin, while the FDA insists on the rabbit test [26][27].
The pharmacopeias general monographs include tests for sterility, endotoxins, microbial limits, volume in the container, uniformity of dosage units, and acceptable particulate matter. However, if provided in a monograph, the specification is not acceptable to FDA and EMA; a side-by-testing must be established.
The EMA provides more comprehensive guidance divided into immunogenicity testing, quality issues, clinical and non-clinical testing, pharmacokinetic modeling, and guidance on changing the manufacturing process of recombinant drugs. In addition, the product-specific guidelines of the EMA are of great value for biosimilar developers [28].
The European and British Pharmacopoeias have developed monographs of several critical biological products defining quality attributes to establish release specifications. The USP has stated that it will not develop monographs for a biologic unless there is stakeholder consensus supporting its creation, including the support of the FDA [29]. The FDA has discouraged the USP from creating biologics monographs to ensure that innovator biologics makers do not use the monograph process to block biosimilar competition by incorporating patented characteristics of their product that are not relevant to safety, purity, or potency, thereby further impacting competition [30]. The FDA also stayed away from creating product-specific monographs, unlike the EMA.

Statistical Modeling

Comparing quality attributes is key in evaluating biosimilars and manufacturing process changes. Different statistical approaches are required, but there is no regulatory consensus on a quantitative and scientifically justified definition and an underlying hypothesis of statistically equivalent quality. Therefore, the comparisons must be made using methods to calculate the operating characteristics for false acceptance and rejection rates of a claim for statistically equivalent quality. These error rates should be as low as possible to allow a meaningful application of a statistical approach in regulatory decision-making.
Statistical data modeling, whenever comparative testing is conducted, is highly controversial. An earlier FDA guideline, “Statistical Approaches to Evaluate Analytical Similarity”, which recommended a rigorous statistical approach for establishing similarity, was withdrawn [31] and replaced with a new guideline [32] in response to many objections, including a citizen petition [33]. The new guideline removed the controversial tier one assessment of quality attributes.
Historically, the WHO had maintained that there is no need for any statistical exercises to compare the data; the most recent WHO guideline states: To mitigate the risks inherent in employing statistical tests on limited samples (false-positive and false-negative conclusions), a comprehensive control strategy must be established for the biosimilar to ensure consistent manufacturing” [9][10]. However, while the guideline supports the quality range approach, it fails to suggest a minimum number of lots needed, as does the FDA guideline [34][35].
The EMA, which had been silent on statistical methods, has described these in detail in its newest guideline that describes the critical approaches for testing biosimilars [35]. While it recommends the interval range approach, it fails to mention the number of lots required and leaves it up to the developer. A statistical testing requires a minimum number of lots to be of any value. Only the FDA guideline suggests using at least 6–10 lots, apart from offering to conform to the suitability of the number of lots required.
A basic understanding of data teaches us that the application of any model is based on the nature of data; if it is normally distributed, then many tests can be applied. The first consideration when applying statistical tests is the essential flexibility of the requirement of “high similarity” to allow for differences if they are clinically meaningless. Statistics may facilitate the detection of differences, e.g., in data distributions or ranges. Still, the determination of whether these differences are clinically relevant is a scientific question that cannot be addressed by a statistical approach alone. Here is a list of various approaches to compare the two products used [35].
  • Visual display. This is most suitable where spectra are produced; most important is the peak locations. This is one of the most important tests as it applies to the critical comparison of primary, secondary, and tertiary structures.
  • MinMax: A MinMax range is defined by a sample’s lowest and highest values. The MinMax test is accepted if the MinMax range of the test sample is within the MinMax range of the reference sample (minTest > minRef and maxTest < maxRef). The MinMax is a conservative approach with a low false acceptance rate but a high false rejection rate.
  • 3Sigma: the 3Sigma range is calculated for the reference sample as (μref-3σref, μref  + 3σref). The 3Sigma test is accepted if the MinMax range of the test sample is within the 3Sigma range. The 3Sigma approach provides a more practical compromise of error rates, further improving with a larger sample size.
  • Tolerance interval (TI): The tolerance interval is calculated for the reference sample as (μ − k*σref, μ + k*σref). The k-factor is calculated two-sided with a confidence level of 0.9 and a proportion of the population covered by the tolerance interval of p = 0.99. The tolerance interval test is accepted if the MinMax range of the test sample is within the tolerance interval calculated for the reference sample. Tolerance interval testing is only usable if the sample size is sufficiently large.
  • Equivalence testing of means (EQT): A two one-sided t-tests’ (TOST) procedure is used to test for equivalency of the means of the reference product and the test product. The equivalence margin is δ = 1.5 SDref (standard deviation of the reference product sample). The Type I error probability is controlled at level α = 0.05 for a conclusion of equivalence. The test is accepted if the (1 − 2α)100% = 90% confidence interval for the difference in the means is within (−δ, +δ). Equivalence testing has a high false rejection rate and, with increasing sample size, a considerable false acceptance rate.
The method of defining the acceptance ranges of critical quality attributes is well described in EMA and FDA quality guidelines. In particular, the FDA biosimilar guidelines thoroughly explain the risk assessment of quality attributes, while EMA guidelines refer to other guiding documents. In general, both FDA, Health Canada, and EMA highlight the importance of state-of-the-art orthogonal analytical methods and in vitro functional/potency tests in the characterization of biosimilars. The quality section of the WHO guidelines needs to be updated to align with the current expectations for analytical characterization and demonstration of biosimilarity.
The quality attributes where statistical modeling is applicable include purity profile, aggregate profile, and function assay profile; glycosylation is better compared with equivalence test; the equivalent testing of mean is least likely to be of any value as used in every regulatory submission.
While the purpose of analytical assessment is to show the difference, it is highly unlikely that a significant difference can be justified; the test limits proposed in all the above tests are arbitrary; it is for this reason, analytical differences are not allowed since, in some cases, a minor change can produce an adverse response. The analytical assessment extends to clinical pharmacology testing, discussed below.

This entry is adapted from the peer-reviewed paper 10.3390/biologics2030014

References

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